Substituted beta-arylamidoacrylic acids

ABSTRACT

CERTAIN SUBSTITUTED B-ARYLAMIDOACRYLIC ACIDS AND A METHOD OF PREPARING THEM ARE DISCLOSED. THESE COMPOUNDS ARE USEFUL AS ANTIINFLAMMATORY AND DIURETIC AGENTS.

United States Patent 3,770,821 SUBSTITUTED ,B-ARYLAMIDOACRYLIC ACIDSRobert Thomas Buckler, Edwardsburg, Mich., and Harold Eugene Hartzler,Elkhart, Ind., assignors to Miles Laboratories, Inc., Elkhart, Ind. N0Drawing. Filed Oct. 16, 1970, Ser. No. 81,622 Int. Cl. C07c 103/30 US.Cl. 260-518 R 27 Claims ABSTRACT OF THE DISCLOSURE Certain substitutedfl-arylamidoacrylic acids and a method of preparing them are disclosed.These compounds are useful as antiinfiammatory and diuretic agents.

SUMMARY OF THE INVENTION Compounds of the present invention correspondto the formula in which R is phenyl, halophenyl, loweralkylphenyl,cyanophenyl, loweralkoxyphenyl, diloweralkylaminophenyl 0r pyridyl; R isloweralkyl or phenyl and R is hydrogen or loweralkyl. The termhalophenyl includes a phenyl radical substituted by from one to threehalogen atoms such as bromine, iodine, chlorine and fluorine. The termsloweralkyl and loweralkoxy include aklyl and alkoxy radicals containingfrom 1 to 4 carbon atoms, inclusive. These compounds possess bothantiinflammatory and diuretic properties. When orally administered toanimals at a dosage of one millimole per kilogram of body weight, theantiinflammatory effect is observed as a significant reduction in theefiusive response to intrapeural injection of Evans Blue: carrageenin.

Compounds included within the scope of this invention can be prepared asshown below wherein R, R and R are as previously defined and R is methylor ethyl:

Thus, the esters of Formula B are acylated with an R-substituted acidchloride according to the known procedure described in Berichte, 42,3912 (1910) to yield the ,B-arylamidoacrylate esters of Formula C whichare carefully saponified with aqueous potassium hydroxide in isopropanolto produce the desired products of Formula A as crystalline solidssoluble in alkali. Alternatively, the t-butyl esters of Formula -D canbe hydrolyzed by dissolving them in sulfuric acid and pouring theresulting solution over crushed ice to obtain the desiredB-arylamidoacrylic acids. Specific embodiments of both procedures areset forth in the examples which follow.

methoxybenzoylamiuo) a methylcrotonate (melting at 97 C.) in 150 ml. of66% aqueous isopropanol contain- 3,770,821 Patented Nov. 6, 1973 iceExample 2 R is methyl, R2 is hydrogen and R is 3,4-dichlorophenyl inFormula A.

A solution of 6.6 grams (0.02 mole) of t-butyl-B-(3,4-dichlorobenzoylamino)crotontae (melting point=-102 C.) in 50 ml. of 98%sulfuric acid was allowed to stand for 3 hours at room temperature andthen poured over crushed ice. The solid which formed was collected,dried and suspended in one liter of boiling water for 5 minutes, thencooled and filtered. Upon recrystallization from benzene, there wasobtained 0.6 gram of fi-(3,4-dichlorobenzoylamino) crotonic acid as awhite solid with a melting point of 167 C. This compound analyzed 5.20%nitrogen compared to 5.11% nitrogen calculated.

Example 3 R is phenyl, R is hydrogen and R is phenyl in Formula A.

A solution of 27 grams (0.092 mole) of ethyl B-benzamidocinnamate(B.P.=195 C. at 0.5 mm. pressure) in 300 ml. of 66% aqueous isopropanolcontaining 6 grams of potassium hydroxide was stirred for 24 hours atroom temperature. The isopropanol was then removed under vacuum and theresidue diluted with water. The insoluble material which formed wasfiltered and the filtrate acidified to produce the desiredfi-benzamidocinnamic acid as a white solid melting at 152 C. The yieldwas 14 grams or 57% of theory. Upon analysis, the acid product was foundto contain 5.02% nitrogen compared to the calculated value of 5.24%nitrogen.

Examples 4-14 By following the saponification procedure described inExample 1, other compounds of Formula A were prepared in which R wasalways methyl, R was always hydrogen and R was as shown in the tablebelow:

Percent nitrogen Ex. Percent No. R C. Cale. Found yield 4 tfluorophenyl155 6.28 6.18 35 5 3-eh1or0pheny1 146 5. 84 5. 72 23 4-chlorophenyl 1495.84 6.06 5 4-bromophenyl 164 4. 93 4.84 7 4-methylphenyl. 150 6.39 6.2937 111 6. 00 5. 82 11 114 5. 67 5. 77 12 136 5. 36 5. 21 15 177 12. 1712.21 2 4-methoxyphenyl 147 5.95 5. 71 13 14.- 4-dimethylaminophenyl 14211.28 11.32 37 The starting crotonate esters employed in the foregomgexamples were as follows:

Example number Starting crotonate ester M.P., C.

1 13.1. at 1 mm.

3 Examples -24 In the same manner as that described in Example 1, stillother compounds corresponding to Formula A were prepared in which R andR were always methyl and R in each example was varied as shown in thefollowing table:

Percent nitrogen Ex. 11.1 Percent No. R C. Cale. Found yield l5 Phenyl155 6. 39 6. 47 16. 4-chlorophenyl 171 5. 52 5. 36 21 17 3iehlorophenyl. 183 4. 86 4. 86 44 18- 3-brornophenyl 172 4. 70 4. 33 3719- 3,5-d1bromophenyl 182 3. 72 3. 7 22 20- lodophenyl 171 4. 06 4. 0552 21 iodophenyl 184 4. 06 4. 10 57 22, 4-pyridyl 170 12. 72 12. 45 1923. i-isopropylphenyl 141 5. 36 5. 36 24 4-t-butylphenyl 167 5. 09 4. 9640 The starting oc-rnethylcrotonate esters used in the previous exampleswere as follows:

EXAMPLES 25-27 By saponifying ethyl 5 benzamido or ethylcrotonaie(melting at 75 C.) as shown in Example 1, the compound of Formula Awherein R was methyl, R was ethyl and R was phenyl was readily obtainedin 37% yield as a crystalline solid with a melting point of 127 C. and anitrogen content of 5.97% compared to 6.01% nitrogen calculated.

Similarly, the saponification of ethyl,B-(4-bromobenzamido)-a-ethylcrotonate (melting point=83 C.) withaqueous KOH in isopropanol produced a 5% yield of the compound ofFormula A in which R was methyl, R was ethyl and R was 4-bromophenyl.Said compound melted at 150 C. and contained 4.40% nitrogen whereas thecalculated value was 4.49% nitrogen.

Likewise, saponification of ethyla-ethyl-fi-(4-isopropylbenzamido)crotonate produced a 33% yield of thecompound of Formula A wherein R was methyl, R was ethyl and R was4-isopropylphenyl which melted at 112 C. and upon analysis was found tocontain 5.04% nitrogen compared to 5.09% nitrogen calculated.

By substituting the appropriate esters of Formula C wherein R and R arepropyl or butyl, R is methyl or ethyl and R is 2,4,5-trichlorophenyl,4-n-butylphenyl, 4-spropoxyphenyl or 4-diethylaminophenyl andsaponifying said esters as shown in Example 1. the corresponding acidsof Formula A are obtained in which R R and R represent the radicalsdesignated.

What is claimed is:

1. A compound of the formula R-CNHC=C-COOH in which: R is a member ofthe group consisting of lower alkyl and phenyl; R is a member of thegroup consisting of hydrogen and lower alkyl; R is a member of the groupconsisting of phenyl, monohalophenyl, dihalophenyl, loweralkylphenyl,loweralkoxyphenyl, diloweralkylaminophenyl; and

wherein loweralkyl and loweralkoxy signify from one to four carbon atomsas applied to R, R and R 2. A compound as in claim 1: ethyl,B-(4-fluorobenzamido)crotonic acid.

3. A compound as in claim 1: methyl ,6-(3-chlorobenzamido)crotonic acid.

4. A compound as in claim 1: methyl B-(4-chlorobenzamido)crotonic acid.

5. A compound as in claim 1: t-butyl fi-(3,4-dichloro benzamido)crotonicacid.

6. A compound as in claim 1: methyl 3-(4-bromobenzamido)crotonic acid.

7. A compound as in claim 1: ethyl B-(4-rnethylbenzamido)crotonic acid.

8. A compound as in claim 1: methyl 5-(4-ethylbenzamido)crotonic acid.

9. A compound as in claim 1: methyl B-(4-isopropylbenzamido crotonicacid.

10. A compound as in claim 1: ethyl ,B-(4-t-butylbenzamido)crotonicacid.

11. A compound as in claim 1: methyl j8-(4-methoxybenzamido)crotonicacid.

12. A compound as in claim 1: methyl,6-(4-dimethylaminobenzamido)crotonic acid.

13. A compound as in claim 1: ethyl fibenzamidoamethylcrotonic acid.

14. A compound as in claim 1: ethylfl-(4-chlorobenzamido)-a-methylcrotonic acid.

15. A compound as in claim 1: ethyl ,B-(3,4-dichlorobenzamidoua-methylcrotonic acid.

16. A compound as in claim 1: ethyl fi-(3-brornobenzamido-ix-methylcrotonic acid.

17. A compound as in claim 1: ethylfl-(3,5-dibromobenzamide)flit-methylcrotonic acid.

18. A compound as in claim 1: ethyl fi-(S-iodobenzamidoM-methylcrotonicacid.

19. A compound as in claim 1: ethylfl-(4-iodobenzamido)-a-methylcrotonic acid.

20. A compound as in claim 1: ethyl fl-(4-methoxybenzamido-a-methylcrotonic acid.

21. A compound as in claim 1: ethyl l8(4-isopropylbenzamido-a-methylcrotonic acid.

22. A compound as in claim 1: ethylfi-(4-t-butylbenzamido)-e-methylcrotonic acid.

23. A compound as in claim 1: ethyl ,B-benzamido-methylcrotonic acid.

24. A compound as in claim 1: ethyl ,6-(4-bromobenzamido-a-ethylcrotonic acid.

25. A compound as in claim 1: ethyl a-ethyl-p-(4-isopropylbenzamido)crotonic acid.

26. A compound as in claim 1: ethyl fl-benzamidocim namic acid.

27. A compound as in claim 1: methyl B-(BA-dichlorobenzamido) crotonicacid.

References Cited Royals, E. B; Advanced Organic Chemistry (1961), pub.by Prentice-Hall, Inc. (QD251R68C16), p. 617 relied on.

LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, AssistantExaminer US. Cl. X.R.

260295.5 R, 465 D, 518 A, 519; 424-263, 304, 319

